Computational models of ethanol-induced neurodevelopmental toxicity across species: Implications for risk assessment

Institute for Risk Analysis and Risk Communication, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105-6099, USA.
Birth Defects Research Part B Developmental and Reproductive Toxicology (Impact Factor: 0.77). 02/2008; 83(1):1-11. DOI: 10.1002/bdrb.20137
Source: PubMed


Computational, systems-based approaches can provide a quantitative construct for evaluating risk in the context of mechanistic data. Previously, we developed computational models for the rat, mouse, rhesus monkey, and human, describing the acquisition of adult neuron number in the neocortex during the key neurodevelopmental processes of neurogenesis and synaptogenesis. Here we apply mechanistic data from the rat describing ethanol-induced toxicity in the developing neocortex to evaluate the utility of these models for analyzing neurodevelopmental toxicity across species. Our model can explain long-term neocortical neuronal loss in the rodent model after in utero exposure to ethanol based on inhibition of proliferation during neurogenesis. Our human model predicts a significant neuronal deficit after daily peak BECs reaching 10-20 mg/dl, which is the approximate BEC reached after drinking one standard drink within one hour. In contrast, peak daily BECs of 100 mg/dl are necessary to predict similar deficits in the rat. Our model prediction of increased sensitivity of primate species to ethanol-induced inhibition of proliferation is based on application of in vivo experimental data from primates showing a prolonged rapid growth period in the primate versus rodent neuronal progenitor population. To place our predictions into a broader context, we evaluate the evidence for functional low-dose effects across rats, monkeys, and humans. Results from this critical evaluation suggest subtle effects are evident at doses causing peak BECs of approximately 20 mg/dl daily, corroborating our model predictions. Our example highlights the utility of a systems-based modeling approach in risk assessment.

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Available from: Julia M Gohlke, Oct 06, 2014
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    • "These studies have reported blood alcohol levels as high as 44–57 mM (0.2–0.27 g/dl) (Burd et al., 2012; Kvigne et al., 2012). We chose to expose to higher levels of ethanol (i.e., ~70 mM) because the developing rodent brain is significantly less sensitive to ethanol than the developing human brain (Gohlke et al., 2008) and neonatal rats are relatively resistant to the depressant effects of ethanol (Hollstedt et al., 1980; Fang et al., 1997). In addition, we previously found that exposure to lower levels of ethanol (i.e., 0.1 g/dl) during the 3rd trimester equivalent has relatively subtle effects on synaptic transmission in the amygdala (Diaz et al., 2014a) and wished to test a higher dose of ethanol that was comparable to that used in other studies of the effect of exposure during this period on anxiety-like behavior in mature rats (Roskam and Koch, 2009). "
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    ABSTRACT: Ethanol consumption during pregnancy produces a wide range of morphological and behavioral alterations known as Fetal Alcohol Spectrum Disorder (FASD). Among the behavioral deficits associated with FASD is an increased probability of developing anxiety disorders. Studies with animal models of FASD have demonstrated that ethanol exposure during the equivalent to the 1st and 2nd trimesters of human pregnancy increases anxiety-like behavior. Here, we examined the impact on this type of behavior of exposure to high doses of ethanol in vapor inhalation chambers during the rat equivalent to the human 3rd trimester of pregnancy (i.e., neonatal period in these animals). We evaluated anxiety-like behavior with the elevated plus maze. Using whole-cell patch-clamp electrophysiological techniques in brain slices, we also characterized glutamatergic and GABAergic synaptic transmission in the basolateral amygdala, a brain region that has been implicated to play a role in emotional behavior. We found that ethanol-exposed adolescent offspring preferred the closed arms over the open arms in the elevated plus maze and displayed lower head dipping activity than controls. Electrophysiological measurements showed an increase in the frequency of spontaneous and miniature excitatory postsynaptic currents in pyramidal neurons from the ethanol group. These findings suggest that high-dose ethanol exposure during the equivalent to the last trimester of human pregnancy can persistently increase excitatory synaptic inputs to principal neurons in the basolateral amygdala, leading to an increase in anxiety-like behaviors. Copyright © 2015. Published by Elsevier Inc.
    Pharmacology Biochemistry and Behavior 08/2015; 137. DOI:10.1016/j.pbb.2015.08.009 · 2.78 Impact Factor
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    • "Such differences may, for example, help in determining the relative impact on brain development of alcohol-induced cell death during synaptogenesis. In a recent publication comparing model results with epidemiological as well as animal literature, the investigators suggest that the developing human neocortex may be more sensitive to the effects of alcohol than the developing rodent neocortex based on the relative increase in the length of neurogenesis and subsequent size of the neocortex in humans (Gohlke et al. 2008) Therefore, interspecies differences in the processes underlying neocortical development must be taken into consideration when extrapolating findings obtained in rodents. "
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    ABSTRACT: Important stages during neurodevelopment include the generation of new nerve cells (i.e., neurogenesis), differentiation and migration of these cells to their final location in the brain, formation of connections with neighboring cells (i.e., synaptogenesis), and cell death of neurons that fail to form the appropriate connections. Research found that alcohol exposure during fetal development can interfere with all of these processes. A systems biology approach using computational models of brain development in different species has been used to determine the relative contributions of alcohol-induced impairment of neurogenesis and synaptogenesis to alcohol-related neurodevelopmental deficits in mice, rats, rhesus monkeys, and humans. The results obtained with these models suggest that alcohol's impact on cell division during neurogenesis results in greater deficits in neuron numbers in the adult than the alcohol-induced increase in cell death during synaptogenesis. In primates, the accelerated development of susceptible brain regions may convey increased sensitivity to alcohol-induced neurodevelopmental deficits. Systems-based approaches, such as the computational models described here, can help to translate research findings obtained at a molecular or cellular level in different species into assessment of risk associated with alcohol exposure during human development.
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